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Abstract
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
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1 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
2 Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, Belgium
3 John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; University of Newcastle, Centre for Information Based Medicine, Callaghan, NSW, Australia; University of Newcastle, Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, Callaghan, NSW, Australia
4 John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; University of Newcastle, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Callaghan, NSW, Australia
5 Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; University of Wisconsin-Milwaukee, Zilber School of Public Health, Milwaukee, WI, USA
6 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany
7 National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA
8 Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK
9 Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tübingen, Tübingen, Germany; German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany
10 German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
11 Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, VIC, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, Australia
12 Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg, Germany; Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg, Germany
13 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Center Hamburg-Eppendorf, Cancer Epidemiology, University Cancer Center Hamburg (UCCH), Hamburg, Germany
14 Epidemiology Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
15 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
16 University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, Oxford, UK
17 University of Sydney, Westmead Institute for Medical Research, Sydney, NSW, Australia
18 Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, University of Melbourne Centre for Cancer Research, Parkville, VIC, Australia
19 University of New Mexico, University of New Mexico Health Sciences Center, Albuquerque, NM, USA; Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada
20 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
21 Department of Oncology and Metabolism, University of Sheffield, Sheffield Institute for Nucleic Acids (SInFoNiA), Sheffield, UK
22 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
23 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
24 University of Cambridge, MRC Epidemiology Unit, School of Clinical Medicine, Cambridge, UK
25 Department of Obstetrics and Gynecology, University Hospitals KU Leuven, University of Leuven, Division of Gynecologic Oncology, Leuven, Belgium; VIB, Vesalius Research Center, Leuven, Belgium; Department of Human Genetics, University of Leuven, Laboratory for Translational Genetics, Leuven, Belgium
26 Cancer Research Huntsman Cancer Institute Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
27 Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
28 Department of Obstetrics and Gynecology, Mayo Clinic, Division of Gynecologic Oncology, Rochester, MN, USA
29 Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
30 Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany
31 Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany; Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Division of Hematology and Oncology, Los Angeles, CA, USA
32 Department of Biostatistics, Kansas University Medical Center, Kansas City, KS, USA
33 Department of Cancer Epidemiology and Prevention Research, Alberta Health Services, Calgary, AB, Canada
34 Curtin University, School of Public Health, Perth, WA, Australia
35 University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, Australia
36 National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA; Institute of Cancer Research, Division of Genetics and Epidemiology, London, UK
37 American Cancer Society, Epidemiology Research Program, Atlanta, GA, USA
38 The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia
39 Department of Health Science Research, Mayo Clinic, Division of Epidemiology, Rochester, MN, USA
40 Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
41 Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Oncology, South General Hospital, Stockholm, Sweden
42 Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Biostatistics and Epidemiology, University of Massachusetts, Amherst, Amherst, MA, USA
43 Department of Oncology, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK
44 Department of Clinical Genetics, St George’s, University of London, London, UK
45 Department of Clinical Science, University of Bergen, Centre for Cancer Biomarkers, Bergen, Norway; Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway
46 The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia
47 Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
48 Department of Cancer Genetics, Oslo University Hospital, Radiumhospitalet, Institute for Cancer Research, Oslo, Norway; University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway; Department of Clinical Molecular Biology, University of Oslo, Oslo University Hospital, Oslo, Norway
49 Department of Human Genetics, University of Leuven, Laboratory for Translational Genetics, Leuven, Belgium; VIB, VIB Center for Cancer Biology, Leuven, Belgium
50 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
51 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
52 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
53 Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center-Oncology Institute, Warsaw, Poland
54 Department of Medicine, Vanderbilt University School of Medicine, Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA
55 Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
56 Department of Anatomic Pathology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
57 University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, UK
58 University of Newcastle, Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, Callaghan, NSW, Australia
59 Department of Gynecology and Obstetrics, Ludwig-Maximilians University of Munich, Munich, Germany
60 Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK; Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus
61 The University of Melbourne, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, Melbourne, VIC, Australia; Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, Australia
62 Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
63 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD, Australia
64 Department of Biochemistry and Molecular Medicine, University of California Davis, Davis, CA, USA
65 Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden
66 University of Newcastle, School of Medicine and Public Health, Callaghan, NSW, Australia
67 Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
68 Department of Medicine, Harvard Medical School, Channing Division of Network Medicine, Brigham and Women’s Hospital, Boston, MA, USA
69 Harvard T.H. Chan School of Public Health, Boston, MA, USA; Dana-Farber Cancer Institute, Boston, MA, USA
70 Department of Obstetrics and Gynaecology, University of Melbourne, Royal Women’s Hospital, Gynaecology Research Centre, Parkville, VIC, Australia
71 Department of Gynaecology and Obstetrics, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Erlangen, Germany
72 Center for Cancer Prevention (CPO-Peimonte), Turin, Italy; Human Genetics Foundation (HuGeF), Turino, Italy
73 Department of Obstetrics and Gynecology, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA
74 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
75 John Hunter Hospital, Hunter Medical Research Institute, Newcastle, NSW, Australia; University of Newcastle, Centre for Information Based Medicine, Callaghan, NSW, Australia; University of Newcastle, Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, Callaghan, NSW, Australia; John Hunter Hospital, Division of Molecular Medicine, Pathology North, Newcastle, NSW, Australia
76 Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia; Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, VIC, Australia
77 Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK; Division of Breast Cancer Research, The Institute of Cancer Research, London, UK
78 Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Karolinska Institutet, Clinical Genetics, Stockholm, Sweden
79 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
80 Department of Obstetrics and Gynaecology, University Hospitals Leuven, Division of Gynecologic Oncology, Leuven Cancer Institute, Leuven, Belgium
81 Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
82 Department of Health Science Research, Mayo Clinic, Division of Biomedical Statistics and Informatics, Rochester, MN, USA
83 Department of Environmental Medicine, Karolinska Institutet, Division of Nutritional Epidemiology, Stockholm, Sweden
84 Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, State Key Laboratory of Oncogene and Related Genes, Shanghai, China
85 Department of Public Health and Primary Care, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK; Department of Oncology, University of Cambridge, Centre for Cancer Genetic Epidemiology, Cambridge, UK
86 University of Oxford, Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, Oxford, UK; University of Birmingham, Institute of Cancer and Genomic Sciences, Birmingham, UK